Modeling and NMR\nData Elucidate the Structure of a\nG‑Quadruplex–Ligand Interaction for a Pu22T-Cyclometalated\nIridium(III) System

Cyclometalated iridium(III) complexes are increasingly\nbeing developed\nfor application in G-quadruplex (GQ) nucleic acid biosensors. We monitored\nthe interactions of a GQ structure with an iridium(III) complex by\nnuclear magnetic resonance (NMR) titrations and subsequently compared\nthe binding site inferred from NMR with binding positions modeled\nby molecular docking and molecular dynamics simulations. When titrated\ninto a solution of G-quadruplex <b>Pu22T</b>, compound <b>1(PF</b><sub><b>6</b></sub>), [Ir(ppy)<sub>2</sub>(pizp)](PF<sub>6</sub>), where ppy is 2-phenylpyridine and pizp is 2-phenylimidazole[4,5f][1,10]phenanthroline,\nhad the greatest impact on the hydrogen chemical shifts of G5, G8,\nG9, G13, and G17 residues of <b>Pu22T</b>, indicating end-stacking\nat the 5′ tetrad. In blind cross-docking studies with Autodock\n4, end-stacking at the 5′ tetrad was found as the lowest energy\nbinding position. AMBER molecular dynamics simulations resulted in\na refined binding position at the 5′ tetrad with improved pi\nstacking. For this model system, <b>Pu22T-1</b>, molecular docking\nand molecular dynamics simulations are tools that are able to predict\nthe experimentally determined binding position.